The present invention relates to 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid amide derivatives, intermediates for preparing the derivatives, and antagonists against angiotensin II (AII) comprising the derivatives.
Angiotensin II is an octapeptide hormone typically relating to hypertension, central nervous system diseases. It is therefore known that inhibition of the activities of angiotensin II is effective for the treatment of the hypertension and the central nervous system diseases.
As angiotensin II inhibitors, there have been developed a renin inhibitor and an angiotensin-converting enzyme (ACE) inhibitor which inhibit the synthesis of angiotensin II. These inhibitors, however, have the problems that they are incapable of inhibiting the activities of angiotensin produced by other types of enzymes than renin and ACE, and that they may exert adverse effects to the other metabolic systems.
Angiotensin II acts through interaction with a specific receptor present in a cell membrane, so that an angiotensin II receptor antagonist which is capable of inhibiting all of the actions of the generated angiotensin II at the level of interaction with the receptor and gives no influence to the other metabolic systems has been desired as an antagonistic agent which is more specific and has less side effects.
Some peptide analogs such as Saralasin have been reported as angiotensin II receptor antagonists, but they are unsatisfactory in their antagonistic activities and also the area of their applications is limited because of their lack of oral absorptivity.
Recently, non-peptidic angiotensin II receptor antagonists have been reported as the agents free of the said problems. Examples of these antagonists are DuP753, PD123177 (Bio-organic & Medical Chemistry Letters, 1(12), 711-716, 1991) and 4,5,6,7-tetrahydro-1H-imidazo[4,5c]pyridine-6-carboxylic acid derivatives disclosed in U.S. Pat. No. 5,091,390, which are represented by the following structural formulae (1), (2), and (3), respectively: ##STR1## wherein for example, R.sup.1 is hydrogen, R.sup.2 is CO.sub.2 H, R.sup.3 is COCH(Ph).sub.2, X is NHCO, R.sup.4 is CO.sub.2 H, and R.sup.6 is CH.sub.3.
Nevertheless, request for the development of a compound having a higher specificity to the angiotensin II receptors and a higher antagonistic activity against angiotensin II is still rising.
In view of the above, the present inventors have extensive researches for wide range of compounds and, as a result, found that some specific 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid amide derivatives have a noticeably high antagonistic activity against angiotensin II and a high specificity to angiotensin II receptors as compared with the known compounds. Based on this finding, the present invention has been attained.